US10604484B2 - Indolone compounds and their use as AMPA receptor modulators - Google Patents

Indolone compounds and their use as AMPA receptor modulators Download PDF

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US10604484B2
US10604484B2 US15/569,313 US201615569313A US10604484B2 US 10604484 B2 US10604484 B2 US 10604484B2 US 201615569313 A US201615569313 A US 201615569313A US 10604484 B2 US10604484 B2 US 10604484B2
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indolin
chloro
phenyl
methyl
compound
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US20180118683A1 (en
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Michael K. Ameriks
Suchitra Ravula
Bradley M. Savall
Devin M. Swanson
Jeannie M. Ziff
Brock T. Shireman
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Janssen Pharmaceutica NV
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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Definitions

  • the present invention is related to compounds having AMPA receptor modulating properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment of diseases associated with AMPA receptor activity in animals, in particular humans.
  • Glutamate is the primary excitatory neurotransmitter in mammalian brain. Glutamatergic signaling participates in a wide range of neural functions including learning and memory, long-term potentiation and synaptic plasticity.
  • Glutamate receptors can be divided into two families.
  • the ionotropic glutamate receptors form ion channels that activate upon binding agonist, opening a pore through the plasma membrane through which cations can flow.
  • the metabotropic glutamate receptors are G-protein-coupled receptors, activating intracellular signal transduction cascades.
  • the ionotropic glutamate receptors can be further subdivided into four sub-families, based upon sequence homology and selectivity to exogenous agonists. These sub-families are the AMPA ( ⁇ -amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid), NMDA (N-methyl-D-aspartate), kainate, and delta receptors.
  • AMPA ⁇ -amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid
  • NMDA N-methyl-D-aspartate
  • kainate and delta receptors.
  • the AMPA subtype of glutamate receptors are glutamate-gated ion channels expressed primarily on postsynaptic membranes of excitatory synapses in the central nervous system. AMPA receptors assemble as tetramers of subunits. Mammals express four AMPA-receptor subunits, called GluA1-GluA4. Each GluA subunit can be expressed in multiple splice variants; the two most prominent splice variants are called flop and flip. GluA subunits freely form functional homo- and hetero-tetramers. The majority of RNA encoding GluA2 subunits is edited post-transcriptionally, altering a genetically-encoded glutamine to arginine. This RNA editing causes AMPA receptors to preferentially form with two GluA2 units, and also prevents calcium entry through the activated receptor.
  • auxiliary proteins which modify the trafficking, localization, gating characteristics, and pharmacology of the AMPA receptor (AMPAR).
  • auxiliary subunits include cytoskeletal and anchoring proteins, other signaling proteins, and several intracellular and transmembrane proteins with unknown function.
  • the wide variety of proteins which can participate in AMPA receptor complexes vastly increases the ability of a neuron to tune the response characteristics of its synapses.
  • TARPs Transmembrane AMPA Receptor Regulatory Proteins
  • TARPs are a fairly recently discovered family of proteins that have been found to associate with and modulate the activity of AMPA receptors.
  • Several TARPs exhibit regiospecific expression in the brain, leading to physiological differentiation of the AMPA receptor activity.
  • TARP ⁇ 2-dependent AMPA receptors are primarily localized in the cerebellum and cerebral cortex while TARP ⁇ 8-dependent AMPA receptors are localized primarily in the hippocampus.
  • AMPA receptors mediate the majority of fast neurotransmission across synaptic gaps. Thus, inhibition or negative modulation of AMPA receptors is an attractive strategy for therapeutic intervention in CNS disorders characterized by excessive neuronal activity.
  • AMPA receptor activity is so ubiquitous within CNS, general antagonism affects most areas of the CNS resulting in undesired effects, such as ataxia, sedation, and/or dizziness, which are shared by all known general AMPA receptor antagonists.
  • Epilepsy affects over 50 million people world-wide, with 30-40% of treated patients being resistant to current pharmacotherapies and only about 8% of treated patients being maintained seizure free. Epilepsy is often defined as when a person has two or more unprovoked epileptic seizures.
  • the International League against Epilepsy (ILAE) defines an epileptic seizure as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.” Seizures are thought to have a number of underlying causalities which adds to the difficulty in treating epilepsy.
  • Seizures have been divided according to their clinical presentation including generalized seizures (absence, atonic, tonic-clonic (grand mal), and myoclonic), simple and complex partial onset seizures, gelastic seizures, dacrystic seizures, and status epilepticus.
  • Current therapies target a variety of mechanisms including GABA ⁇ -aminobutyric acid) receptor agonism, T-type calcium channel blockers, sodium channel modulators, synaptic vesicle protein SV2A modulation, and inhibition of GABA transaminase. More recently, AMPA receptor antagonists have been investigated for treatment of seizures as well.
  • AMPA receptor antagonists are known anticonvulsant agents. Typically, AMPA receptor antagonists have very narrow therapeutic dosing windows; the doses needed to obtain anti-convulsant activity are close to or overlap with doses at which undesired effects are observed. (Michael A. Rogawski.
  • Glutamate as an excitatory neurotransmitter has been known to induce neurotoxicity by, for example, abnormal excitation of central nerves.
  • Neurotoxicity is an adverse structural or functional change in the nervous system, and can take the form of subtle or gross biochemical changes, axonal degeneration, dendritic pruning or sprouting, loss or rearrangement of synapses, or cell death.
  • Numerous nervous diseases involve a neurotoxic component, including and not limited to cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain and diabetic neuropathy.
  • ALS amyotrophic lateral sclerosis
  • AIDS nervous disturbance including and not limited to cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain and diabetic neuropathy.
  • WO2000001376 suggests that inhibitors of the interaction of glutamate with the AMPA and/or kainate receptor complex could be useful in treating demyelinating disorders such as encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, a secondary demyelinating disorder; for example, CNS lupus erythematodes, polyarteritis nodosa, Sjogren syndrome, sarcoidosis, isolated cerebral vasculitis, etc.
  • demyelinating disorders such as encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome
  • Hippocampus links the limbic system to frontal cortex, thereby linking emotion to cognition (Small et al, Nat. Rev. Neurosci. 12:585-601, 2011).
  • a meta-analysis of post-mortem neuro-pathology studies suggests that hippocampal volume is reduced in volume in patients with mood disorders (Harrison, Brain 125:1428-1449, 2002).
  • Hippocampal neurons are particularly susceptible to stress-related atrophy. Pathological states characterized by excessive activity within hippocampus may be improved by a therapeutic intervention that selectively reduces hippocampal excitability. Modulation of neuronal excitability within hippocampus may provide a therapeutic benefit in mood disorders.
  • Intrahippocampal administration of ZD7288, an HCN channel inhibitor slowed brainstem-stimulated theta rhythm in anesthetized rat and also increased the amount of time that rats spent in the open arms of an elevated plus maze (Yeung et al., Hippocampus 23:278-286, 2013).
  • Intrahippocampal administration of phenytoin, a voltage-gated sodium channel inhibitor and anticonvulsant showed similar effects on brainstem-stimulated theta rhythm frequency in anesthetized rat and was anxiolytic in conscious rat (Yeung et al., Neuropharmacology 62: 155-160, 2012).
  • Hippocampal overactivity has been observed in patients suffering from schizophrenia (Heckers and Konradi, Curr Top Behav Neurosci. 4:529-553, 2010). The degree of hyperactivity was be positively correlated to the severity of the symptoms (Tregellas et al., Am J Psychiatry 171: 549-556, 2014). Hypermetabolism in hippocampus (esp. CA1 region) correlates with disease progression in at-risk individuals, and with disease severity in patients diagnosed with schizophrenia (Schobel et al., Arch Gen Psych, 66:938-946, 2009). This over-activity, combined with the sensitivity of hippocampal neurons to excitotoxic damage, may lead to the observed decrease in hippocampal volume in schizophrenic patients. Neuroprotection in prodromal and early stages may prevent progressive damage (Kaur and Cadenhead, Curr Top Behav Neurosci, 2010).
  • compounds which are AMPA receptor modulators are AMPA receptor modulators.
  • compounds which modulate certain TARP dependent AMPA receptors are suitable for treatment of conditions involving AMPA receptor activity, and for treatment of conditions involving selective modulation of TARP dependent AMPA receptor activity, thereby allowing for treatment of conditions such as, inter alia, abnormal neurotransmission across synaptic gaps, excessive neuronal activity, abnormal excessive or synchronous neuronal activity in the brain, neurotoxicity (e.g., adverse structural or functional changes in the nervous system, subtle or gross biochemical changes, axonal degeneration, dendritic pruning or sprouting, loss or rearrangement of synapses, or cell death), neuronal excitability within hippocampus, neuronal excitotoxicity, hippocampal overactivity, and the like.
  • neurotoxicity e.g., adverse structural or functional changes in the nervous system, subtle or gross biochemical changes, axonal degeneration, dendritic pruning or sprouting, loss or rearrangement of synapses, or cell death
  • the compounds of Formula (I) are compounds selected from those species described or exemplified in the detailed description below.
  • the invention relates to enantiomers and diastereomers of the compounds of Formula (I), as well as their pharmaceutically acceptable salts.
  • the invention relates to pharmaceutical compositions, comprising an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I).
  • compositions according to the invention may further comprise one or more pharmaceutically acceptable excipients.
  • the chemical embodiments of the present invention are useful as AMPA receptor modulators.
  • the invention is directed to a method for modulating AMPA receptor activity, including when such receptor is in a subject, comprising exposing AMPA receptor to an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I).
  • the invention is directed to a method of treating a subject suffering from, or diagnosed with a disease, disorder, or medical condition mediated by AMPA receptor activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I), pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of compounds of Formula (I). Additional embodiments of methods of treatment are set forth in the detailed description.
  • the method of studying isotopically labeled compounds of Formula (I) in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • Additional embodiments of this invention include methods of making compounds of Formula (I), pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I), pharmaceutically acceptable prodrugs of compounds of Formula (I), and pharmaceutically active metabolites of Formula (I).
  • An object of the present invention is to overcome or ameliorate at least one of the disadvantages of the conventional methodologies and/or prior art, or to provide a useful alternative thereto.
  • compositions comprising an effective amount of a compound of Formula (IA), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (IA), pharmaceutically acceptable prodrugs of compounds of Formula (IA), and pharmaceutically active metabolites of Formula (IA).
  • the compounds of Formula (IA), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (IA), pharmaceutically acceptable prodrugs of compounds of Formula (IA), and pharmaceutically active metabolites of Formula (IA) are useful for modulating AMPA receptor activity, as well as treating any condition described herein.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is H.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is halo.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is —Br or —F.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 6 is H.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 6 is H, halo, —CH 3 , —CF 3 , —OCH 3 , —OCF 3 , and —CN.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 and R 6 are H.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 3 , R 4 , and R 5 are defined according to (A).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 4 , and R 5 are defined according to (A), and R 3 is H, —Cl, —CN, —CH 3 , or —CH 2 CN.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 4 , and R 5 are defined according to (A), and R 3 is H, —CN.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 and R 3 are defined according to (A), and R 5 is —Cl, —Br, —F, —CH 2 CN, —CH(CH 3 )CN, —OCF 2 H, —OCF 3 , —CH ⁇ CH 2 , —O—CH 2 CF 3 , —O—CH 2 CF 2 H, —OCH(CH 3 )CF 3 , —CF 3 , —O-benzyl, —CO 2 CH 3 , —OCH 2 CN, cyclopropyl, phenyl,
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 and R 3 , are defined according to (A), and R 5 is —Cl, —Br, —F, —CH 2 CN, —CH(CH 3 )CN, —OCF 2 H, or —OCF 3 .
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 3 , R 4 , and R 5 are defined according to (B).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 3 , R 4 , and R 5 are defined according to (C).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 and Z 2 are C, and R 2 , R 3 , R 4 , and R 5 are defined according to (D).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 is N, Z 2 is C, and R 2 , R 4 , and R 5 are defined according to (E).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 is C, Z 2 is N, and R 2 , R 4 , and R 5 are defined according to (E).
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 1 is C, Z 2 is N, R 4 is H, R 3 is H or —CF 3 , R 5 is defined according to (E), and R 2 is —Cl, —OCH 3 , —OCF 3 , —OCF 2 H, or —CH 3 .
  • An additional embodiment of the invention is a compound of Formula (I) wherein Z 2 is C, Z 1 is N, R 4 is H, R 5 is defined according to (E), and R 2 is —Cl, —OCH 3 , or —CH 3 .
  • An additional embodiment of the invention is a compound of Formula (II), and pharmaceutically acceptable salts, N-oxides, or solvates thereof:
  • An additional embodiment of the invention is a compound of Formula (II) wherein R 6 is —H, —F, or —CH 3
  • An additional embodiment of the invention is a compound of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof, as defined in (A), having the structure of Formula (II),
  • An additional embodiment of the invention is a compound of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof, as defined in (B), having the structure of Formula (II),
  • An additional embodiment of the invention is a compound of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof, as defined in (C), having the structure of Formula (II),
  • An additional embodiment of the invention is a compound of Formula (III), and pharmaceutically acceptable salts, N-oxides, or solvates thereof:
  • An additional embodiment of the invention is a compound of Formula (IA), and pharmaceutically acceptable salts, N-oxides, or solvates thereof:
  • An additional embodiment of the invention is a compound of Formula (IA) wherein
  • a compound selected from the group consisting of compounds of Formula (II), Formula (III), or Formula (IA), or a combination thereof.
  • a further embodiment of the current invention is a compound as shown below in Table 1.
  • a further embodiment of the current invention is a compound as shown below in Table 2.
  • An additional embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising and effective amount of at least one compound of Formula (IA) (as well as Formula (II), and Formula (III), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (IA) (as well as Formula (II), and Formula (III), pharmaceutically acceptable prodrugs of compounds of Formula (IA) (as well as Formula (II), and Formula (III), and pharmaceutically active metabolites of Formula (IA) (as well as Formula (II), and Formula (III); and at least one pharmaceutically acceptable excipient.
  • An additional embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising and effective amount of at least one compound in Table 1, as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Table 1, pharmaceutically acceptable prodrugs of compounds of Table 1, and pharmaceutically active metabolites of Table 1; and at least one pharmaceutically acceptable excipient.
  • An additional embodiment of the invention is a pharmaceutical composition comprising and effective amount of at least one compound in Table 2, as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Table 2, pharmaceutically acceptable prodrugs of compounds of Table 2, and pharmaceutically active metabolites of Table 2; and at least one pharmaceutically acceptable excipient.
  • isotopic variations of compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), such as, e.g., deuterated compounds of Formula (I).
  • pharmaceutically acceptable salts, N-oxides or solvates of the isotopic variations of the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)).
  • pharmaceutically acceptable prodrugs of the isotopic variations of the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), and pharmaceutically active metabolites of the isotopic variations of the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)).
  • An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by AMPA receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from compounds of Formula (I):
  • in one embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by AMPA receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from a compound of Formula (IA) (as well as Formula (II), and Formula (III), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (IA) (as well as Formula (II), and Formula (III), pharmaceutically acceptable prodrugs of compounds of Formula (IA) (as well as Formula (II), and Formula (III), and pharmaceutically active metabolites of Formula (IA) (as well as Formula (II), and Formula (III).
  • a compound of Formula (IA) as well as Formula (II), and Formula (III
  • pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (IA) as well as Formula (II), and Formula (III
  • the AMPA subtype of glutamate receptors are glutamate-gated ion channels expressed primarily on postsynaptic membranes of excitatory synapses in the central nervous system. AMPA receptors assemble as tetramers of subunits. Mammals express four AMPA-receptor subunits, called GluA1-GluA4. In their native environment, the pore-forming GluA tetramers directly or indirectly associate with numerous auxiliary proteins. The wide variety of proteins which can participate in AMPA receptor complexes vastly increases the ability of a neuron to tune the response characteristics of its synapses.
  • AMPA receptors mediate the majority of fast neurotransmission across synaptic gaps. However, since AMPA receptor activity is so ubiquitous within CNS, general antagonism affects most areas of the CNS resulting in undesired effects, such as ataxia, sedation, and/or dizziness, which are shared by all known general AMPA receptor antagonists.
  • TARP ⁇ 8-associated AMPA receptor complexes provides effective therapeutic agents which also avoid or reduce the side-effects associated with the administration of non-selective AMPA receptor modulators.
  • TARP ⁇ 8 is primarily expressed in the hippocampus and the cortex, while TARP ⁇ 2 is primarily expressed in the cerebellum.
  • selective modulation of TARP ⁇ 8 potentially avoids modulation of TARP ⁇ 2-associated AMPA receptor complexes, which are more prevalent in the cerebellum, thereby reducing side effects associated with general (non-TARP dependent/non-selective) AMPA antagonism.
  • selective modulation of TARP ⁇ 8-associated AMPA receptor complexes is contemplated as an effective anti-seizure/anti-epileptic therapeutic with reduced the side effects (e.g. sedation, ataxis, and/or dizziness) associated with general (non-TARP dependent/non-selective) AMPA antagonists.
  • side effects e.g. sedation, ataxis, and/or dizziness
  • side effects e.g. sedation, ataxis, and/or dizziness
  • reduction of hippocampal over-excitability using selective modulation of TARP ⁇ 8-associated AMPA receptor complexes may lead to normalization of the symptoms of schizophrenia, and it may protect against the subsequent decline in hippocampal volume.
  • selectively attenuating hippocampal excitability via selective modulation of TARP ⁇ 8-associated AMPA receptor complexes, could provide therapeutic benefit to patients with bipolar disorder.
  • selective modulation of TARP ⁇ 8-associated AMPA receptor complexes within the hippocampus may provide an effective anxiolytic.
  • compounds which are selective modulators of TARP ⁇ 8-associated AMPA receptor complexes ameliorate and/or eliminate the side effects (e.g. sedation, ataxis, and/or dizziness) of general (non-TARP dependent/non-selective) AMPA receptor modulators.
  • provided herein are compounds which selectively modulate the activity of complexes comprising GluA1 receptors associated with the protein TARP ⁇ 8.
  • selective modulation of TARP ⁇ 8-associated AMPA receptor complexes refers to selective antagonism of TARP ⁇ 8-associated AMPA receptor complexes.
  • selective modulation of TARP ⁇ 8-associated AMPA receptor complexes refers to selective partial inhibition of TARP ⁇ 8-associated AMPA receptor complexes.
  • selective antagonism of TARP ⁇ 8-associated AMPA receptor complexes refers to negative allosteric modulation of TARP ⁇ 8-associated AMPA receptor complexes.
  • the invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by AMPA receptor activity. These methods are accomplished by administering to the subject a compound of the invention.
  • the compounds described herein are selective for modulation of TARP ⁇ 8 associated AMPA receptor complexes.
  • An AMPA receptor mediated disease, disorder or condition includes and is not limited to cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, various neurodegenerative diseases, various mental diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy (Guillain Barre syndrome), chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, a secondary demyelinating disorder (for example, CNS lupus erythematodes, polyarteritis nodos
  • an AMPA receptor mediated disease, disorder or condition is a condition related to hippocampal hyperexcitability.
  • methods to selectively dampen hippocampal activity in the brain comprising administration of compounds described herein to a subject in need thereof.
  • methods for the treatment of an AMPA receptor mediated disease, disorder or condition which is depression comprising administration of compounds described herein to a subject in need thereof.
  • depression includes and is not limited to major depression, psychotic depression, persistent depressive disorder, post-partum depression, seasonal affective disorder, depression which is resistant to other anti-depressants, manic-depression associated with bipolar disorder, post traumatic stress disorder, and the like.
  • provided herein are methods for the treatment of an AMPA receptor mediated disease, disorder or condition which is post traumatic stress disorder (PTSD) comprising administration of compounds described herein to a subject in need thereof.
  • methods for the treatment of an AMPA receptor mediated disease, disorder or condition which is epilepsy, schizophrenia, or prodromal schizophrenia comprising administration of compounds described herein to a subject in need thereof.
  • methods for the treatment of an AMPA receptor mediated disease, disorder or condition which is a cognitive disorder comprising administration of compounds described herein to a subject in need thereof.
  • cognitive disorder includes and is not limited to mild cognitive impairment, amnesia, dementia, delirium, cognitive impairment associated with anxiety disorders, mood disorders, psychotic disorders and the like.
  • administration of a compound of the invention, or pharmaceutically acceptable salt thereof is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. In some embodiments, an alkyl group is a C 1-6 alkyl group. In some embodiments, an alkyl group is a C 1-5 alkyl group.
  • alkyl groups include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain and having at least one of the hydrogens replaced with a halogen.
  • a haloalkyl group is a C 1-6 haloalkyl group.
  • a haloalkyl group is a C 1-5 haloalkyl group.
  • One exemplary substitutent is fluoro.
  • Preferred substituted alkyl groups of the invention include trihalogenated alkyl groups such as trifluoromethyl groups.
  • Haloalkyl includes and is not limited to —CF 3 , —CH 2 F, —CHF 2 , —CH 2 Cl, —CH 2 —CF 3 , and the like.
  • cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 8 carbon atoms.
  • examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • alkoxy includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule.
  • an alkoxy group is a C 1-6 alkoxy group.
  • an alkoxy group is a C 1-5 alkoxy group.
  • Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
  • haloalkoxy includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule and having at least one of the hydrogens replaced with a halogen.
  • a haloalkoxy group is a C 1-6 haloalkoxy group.
  • a haloalkoxy group is a C 1-5 haloalkoxy group.
  • Haloalkoxy includes and is not limited to —OCF 3 , —OCH 2 F, —OCHF 2 , —OCH 2 Cl, —O—CH 2 —CF 3 , and the like.
  • thiophenyl and “thienyl” are used interchangeably.
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • halo represents chloro, fluoro, bromo, or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
  • buffer solution or “buffer” solution are used herein interchangeably according to their standard meaning. Buffered solutions are used to control the pH of a medium, and their choice, use, and function is known to those of ordinary skill in the art. See, for example, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry, p. 261, 5 th ed. (2005), describing, inter alia, buffer solutions and how the concentrations of the buffer constituents relate to the pH of the buffer. For example, a buffered solution is obtained by adding MgSO 4 and NaHCO 3 to a solution in a 10:1 w/w ratio to maintain the pH of the solution at about 7.5.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.”
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, and a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
  • Certain examples contain chemical structures that are depicted as an absolute enantiomer but are intended to indicate enatiopure material that is of unknown configuration.
  • (R*) or (S*) is used in the name to indicate that the absolute stereochemistry of the corresponding stereocenter is unknown.
  • a compound designated as (R*) refers to an enantiopure compound with an absolute configuration of either (R) or (S).
  • the structures are named using (R) and (S).
  • Compounds of the invention may also exist as “rotamers,” that is, conformational isomers that occur when the rotation leading to different conformations is hindered, resulting a rotational energy barrier to be overcome to convert from one conformational isomer to another.
  • any formula given herein is intended to refer also to hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • Certain compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), or pharmaceutically acceptable salts of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) may be obtained as solvates.
  • Solvates include those formed from the interaction or complexation of compounds of the invention with one or more solvents, either in solution or as a solid or crystalline form. In some embodiments, the solvent is water and the solvates are hydrates.
  • certain crystalline forms of compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) or pharmaceutically acceptable salts of compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) may be obtained as co-crystals.
  • compounds of Formula (I) were obtained in a crystalline form.
  • crystalline forms of compounds of Formula (I) were cubic in nature.
  • pharmaceutically acceptable salts of compounds of Formula (I) were obtained in a crystalline form.
  • compounds of Formula (I) were obtained in one of several polymorphic forms, as a mixture of crystalline forms, as a polymorphic form, or as an amorphous form. In other embodiments, compounds of Formula (I) convert in solution between one or more crystalline forms and/or polymorphic forms.
  • references to a compound herein stands for a reference to any one of: (a) the actually recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
  • reference herein to a compound such as R—COOH encompasses reference to any one of, for example, R—COOH (s) , R—COOH (sol) , and R—COO ⁇ (sol) .
  • R—COOH (s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation
  • R—COOH (sol) refers to the undissociated form of the compound in a solvent
  • R—COO ⁇ (sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R—COOH, from a salt thereof, or from any other entity that yields R—COO ⁇ upon dissociation in the medium being considered.
  • an expression such as “exposing an entity to compound of formula R—COOH” refers to the exposure of such entity to the form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such exposure takes place.
  • an expression such as “reacting an entity with a compound of formula R—COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R—COOH that exists, or exist, in the medium in which such reacting takes place.
  • a zwitterionic compound is encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities.
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign.
  • aminoethanoic acid (the amino acid glycine) has the formula H 2 NCH 2 COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion+H 3 NCH 2 COO ⁇ .
  • Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 125 I, respectively.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium or tritium (i.e., 2 H, 3 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof.
  • substituent S example is one of S 1 , S 2 , and S 3
  • this listing refers to embodiments of this invention for which S example is S 1 ; S example is S 2 ; S example is S 3 ; S example is one of S 1 and S 2 ; S example is one of S 1 and S 3 ; S example is one of S 2 and S 3 ; S example is one of S 1 , S 2 and S 3 ; and S example is any equivalent of each one of these choices.
  • C i-j when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized.
  • the term C 1-3 refers independently to embodiments that have one carbon member (C 1 ), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • C n-m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ⁇ N ⁇ m, with m>n.
  • Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • the invention includes also pharmaceutically acceptable salts of the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.
  • pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of compounds represented by Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. It should possess the desired pharmacological activity of the parent compound. See, generally, G. S. Paulekuhn, et al., “Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database”, J. Med. Chem., 2007, 50:6665-72, S. M.
  • a compound of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phen
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like
  • an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • suitable salts include organic salts derived from amino acids, such as N-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as N-methyl-D-glucamine, lysine, choline, glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as tromethamine, benzylamines, pyrrolidines, piperidine, morpholine, and piperazine
  • inorganic salts derived
  • the invention also relates to pharmaceutically acceptable prodrugs of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “ Design of Prodrugs ”, ed. H. Bundgaard, Elsevier, 1985.
  • Exemplary prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)).
  • amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • prodrugs may be produced, for instance, by derivatizing free carboxyl groups of structures of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) as amides or alkyl esters.
  • amides include those derived from ammonia, primary C 1-6 alkyl amines and secondary di(C 1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties.
  • amides include those that are derived from ammonia, C 1-3 alkyl primary amines, and di(C 1-2 alkyl)amines.
  • esters of the invention include C 1-7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(C 1-6 alkyl) esters.
  • Preferred esters include methyl esters.
  • Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs.
  • Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs.
  • Prodrugs of this type may be prepared as described in Robinson et al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
  • the present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)), which may also be used in the methods of the invention.
  • a “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) (as applicable) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci.
  • the compounds of Formula (I) (as well as Formula (II), Formula (III), and Formula (IA)) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the AMPA receptor in the methods of the invention.
  • the compounds may act as antagonists, agonists, or inverse agonists.
  • modulators include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize, or down-regulate the AMPA receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate AMPA receptor expression or activity.
  • pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • pharmaceutically acceptable excipient refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a agent and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • subject includes humans.
  • human includes humans.
  • patient includes humans.
  • subject includes human, patient, and “subject” are used interchangeably herein.
  • treating refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • a therapeutically effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • a “therapeutically effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
  • an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 10 mg to about 2.5 g/day.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.
  • the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • the additional active ingredients may be coadministered separately with a compound of the invention or included with such an agent in a pharmaceutical composition according to the invention.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of at least one compound in accordance with the invention; and (b) a pharmaceutically acceptable excipient.
  • compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art.
  • the compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.
  • Oral tablets may include a compound according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
  • the active agents of this invention may also be administered by non-oral routes.
  • the compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • a phenol compound of formula (IId), where Z 1 and Z 2 are C, R 5 is —Cl, and R a is H, is protected with a protecting group (PG), where PG is a conventional phenol protecting group, such as methoxymethyl ether (MOM), under conditions known to one skilled in the art. Subsequent metalation followed by halogenation provides a compound of formula (IIId).
  • PG protecting group
  • MOM methoxymethyl ether
  • reaction of a protected phenol with a strong base such as n-butyllithium (n-BuLi), and the like, at a temperature such as ⁇ 78° C., in a suitable solvent such as THF, and the like, and an electrophilic halogen source such as iodine provides a compound of formula (IIId), where Hal 1 is —I, and PG is methoxymethyl ether.
  • a compound of formula (IV) where R 2a is —OH.
  • reaction with an acid such as HCl, in a solvent such as dioxane, ether and the like, at temperatures ranging from 20-50° C. affords a compound of formula (IV).
  • the acid is HCl in dioxane.
  • a compound of formula (IId), where one Z 1 or Z 2 is N, R 5 is —Cl, and R a is H is also protected with a suitable protecting group, employing methods previously described to provide a compound of formula (IIId).
  • a compound of formula (III) is reacted under metalation/halogenation conditions previously described to provide a compound of formula (IV) where one Z 1 or Z 2 is N, R 5 is —Cl, R a is H, and Hal 1 is —I. Removal of the protecting group in a compound of formula (III) using conditions known to one skilled in the art affords a compound of formula (IV), where R 2a is —OH.
  • a compound of formula (IId), where R a is —C 1-5 haloalkyl and R 5 is —Cl is deprotonated with a strong base such as n-butyllithium (n-BuLi), and the like, at a temperature such as ⁇ 78° C., in a suitable solvent such as THF, and the like, and an electrophilic halogen source such as I 2 , Br 2 , N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), and the like, to provide a compound of formula (IV), where Hal 1 is —I or —Br, R 2a is —C 1-5 haloalkoxy, and R 5 is —Cl.
  • a strong base such as n-butyllithium (n-BuLi), and the like
  • a benzonitrile compound of formula (IIIa), where R 4a is —CN, is deprotonated with a mixed Zn/Li base such as zinc chloro 2,2,6,6-tetramethylpiperidide lithium chloride complex (TMPZnCl*LiCl), in a suitable solvent such as THF, employing conventional heating at a temperature such as 60° C. for a period of 16 h, and then treated with an electrophile such as iodine at a temperature such as 60° C. to provide a compound of formula (IV) where R 4 is —CN, and Hal 1 is —I.
  • a mixed Zn/Li base such as zinc chloro 2,2,6,6-tetramethylpiperidide lithium chloride complex (TMPZnCl*LiCl)
  • THF zinc chloro 2,2,6,6-tetramethylpiperidide lithium chloride complex
  • a compound of formula (V), where R 5 is halo, Z 1 or Z 2 are C or N (wherein both Z 1 and Z 2 cannot be N), Hal 1 is —I, and R a is H; is treated with an alkylating reagent such as sodium chlorodifluoroacetate or diethyl (bromodifluoromethyl)phosphonate, in the presence of a base such as potassium hydroxide, cesium carbonate, and the like, in a suitable solvent such as acetonitrile, DMF, water, and the like, employing conventional heating and cooling, at temperatures ranging from ⁇ 78° C. to 100° C., to provide a difluoromethoxy compound of formula (VI) where R 2 is —C 1-5 haloalkoxy.
  • an alkylating reagent such as sodium chlorodifluoroacetate or diethyl (bromodifluoromethyl)phosphonate
  • a base such as potassium hydroxide, cesium carbonate, and the like
  • an alkylating reagent such as dibromodifluoromethane, and the like
  • a bromodifluoromethoxy compound of formula (VII) is treated with a fluoride source such as silver tetrafluoroborate, in a suitable solvent such as DCM, employing conventional cooling, at temperatures ranging from ⁇ 78° C. to rt, to provide a trifluoromethoxy compound of formula (VI) where R 2 is —C 1-5 haloalkoxy.
  • a fluoride source such as silver tetrafluoroborate
  • a compound of formula (VIII), where R 2 is halo, R 5a is —CH 3 , and Hal 1 is —I is treated with a brominating reagent such as NBS, in the presence of a suitable catalyst such as AIBN, ABCN, and the like, in a suitable solvent such as carbon tetrachloride, employing conventional heating, at a temperature such as 90° C., to provide a methylbromide compound where R 5a is —CH 2 Br.
  • an alkylating agent such as iodomethane, 1,2-dibromoethane, 1,3-dibromopropane, and the like
  • a methylbromide compound of formula (IX) where R 2 is -halo, R 5a is —CH 2 Br, and Hal 1 is —I is reacted in a displacement reaction with a commercially available or synthetically accessible optionally substituted 5-6 membered heterocyclic amine, such as morpholine, piperidine, N-methylpiperazine, and the like, in the presence of base such as triethylamine, in a suitable solvent such as DCM to afford a compound of formula (X), where R 2 is —Cl, R 5 is an optionally substituted 5-6 membered heterocyclic amine, such as morpholinyl, piperidinyl, or N-methylpiperazinyl, and Hal 1 is —I.
  • a commercially available or synthetically accessible optionally substituted 5-6 membered heterocyclic amine such as morpholine, piperidine, N-methylpiperazine, and the like
  • base such as triethylamine
  • a suitable solvent such as
  • a compound of formula (XI), where R 3 is —Br, and Hal 1 is —Br is aminated under conditions known to one of skill in the art, to provide a compound of formula (XII).
  • a compound of formula (XI), where R 3 is —Br, and Hal 1 is —Br is treated with a suitable primary or secondary cyclic or acyclic amine, in the presence of a palladium catalyst such as Pd 2 (dba) 3 , and the like, a phosphine ligand such as BINAP, and the like, a suitable base such as sodium tert-butoxide (NaOt-Bu), and the like, in a solvent such as toluene, and the like, employing conventional or microwave heating, at a temperature such as 140° C., to provide a compound of formula (XII), where R 2 is —Cl, R 3 is 4-methoxypiperdinyl, and Hal 1
  • a compound of formula (VII), where R 2 is —Cl, R 3 is —Br, and Hal 1 is —Br, is coupled under Suzuki reaction conditions known to one skilled in the art with a commercially available or synthetically accessible suitable aryl or heteroaryl boronic acid or boronic ester, in the presence of a palladium catalyst such as PdCl 2 (dppf)-CH 2 Cl 2 , PdCl 2 (dtbpf), and the like, a suitable base such a potassium phosphate, and the like, in a solvent such as dioxane, water, or a mixture thereof, employing conventional or microwave heating, at a temperature such as 100° C., to provide a compound of formula (VIII), where R 2 is —Cl, R 3 is an optionally substituted aryl or heteroaryl, and Hal 1 is —Br.
  • a palladium catalyst such as PdCl 2 (dppf)-CH 2 Cl 2 , PdCl 2 (d
  • a compound of formula (XIV) is treated with hydrazine, in a suitable solvent such as n-butanol, employing conventional heating, at a temperature such as 80° C., followed by treatment with a base such as trimethylamine, and further heating at a temperature such as 100° C., to provide a compound of formula (XV),
  • Hal 2 is —Br and R 6 is C 1-5 haloalkyl, C 1-5 haloalkoxy, or —C 1-5 alkoxy.
  • an indolone compound of formula (XVI), where R 6 is halo, —C 1-5 alkyl, or —CN is treated with an electrophilic halogen source such as NBS, in a solvent such as TFA, employing conventional cooling, at a temperature such as 0° C., to provide a compound of formula (XV), where Hal 2 is —Br and R 6 is halo, —C 1-5 alkyl, or —CN.
  • a palladium catalyst such as PdCl 2 (dppf)-CH 2 Cl 2 , Pd 2 (d
  • a compound of formula (XV), where Hal 2 is —Br, R 1 and R 6 are as defined in Formula (I), is coupled in a Suzuki reaction with a commercially available or synthetically accessible suitably substituted phenyl or pyridyl boronic acid or ester, in the presence of a palladium catalyst such as PdCl 2 (dppf)-CH 2 Cl 2 , PdCl 2 (dtbpf), Pd 2 (dba) 3 , and the like, with our without dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine, a suitable base such a potassium phosphate, and the like, in a solvent such as toluene, dioxane, water, or a mixture thereof, employing conventional or microwave heating, at a temperature such as 100° C., to provide a compound of Formula (I).
  • a palladium catalyst such as PdCl
  • Compounds of Formula (I) may be converted to their corresponding salts using methods known to one of ordinary skill in the art.
  • an amine of Formula (I) is treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et 2 O, CH 2 Cl 2 , THF, CH 3 OH, chloroform, or isopropanol to provide the corresponding salt form.
  • trifluoroacetic acid or formic acid salts are obtained as a result of reverse phase HPLC purification conditions.
  • Crystalline forms of pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non-polar solvents (including mixtures of non-polar solvents).
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • Compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as mixtures of various forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers may be separated using conventional methods such as chromatography or crystallization.
  • reaction mixtures were magnetically stirred at rt (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na 2 SO 4 or MgSO 4 . Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.
  • “flowed through a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 Touch Syringe Pump that is in line via 1/16′′ PTFE (PolyTetraFluoroEthylene) tubing to a LTF-VS mixer (Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwise indicated.
  • SFC supercritical fluid high performance liquid chromatography
  • Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
  • NMR Nuclear magnetic resonance
  • Step B 3-Chloro-4-iodo-5-(methoxymethoxy)pyridine
  • Step B 7-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one
  • Step C 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)indolin-2-one
  • Example 7-Example 80 are prophetic compounds and may be made in a manner analogous to Example 2.
  • Step B 2-(3-Chloro-2-(2-oxoindolin-5-yl)phenyl)-2-methylpropanenitrile
  • Example 82-Example 114, Example 116, and Example 120 are prophetic compounds and may be prepared in a manner analogous to Example 1.
  • Step B 5-(2-Chloro-6-(difluoromethoxy)phenyl)-7-fluoroindolin-2-one
  • Step B 5-(2-Chloro-3-(4-methoxypiperidin-1-yl)phenyl)-7-fluoroindolin-2-one
  • the title compound was prepared in a manner analogous to Example 2, substituting 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one for 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one and 3,5-dichloro-4-iodo-2-(trifluoromethyl)pyridine for 1-bromo-3-chloro-2-iodobenzene.
  • Step B 5-(2-Chloro-3-(4-methoxypiperidin-1-yl)phenyl)indolin-2-one
  • Examples 180-184 are prophetic compounds and may be prepared in a manner analogous to Example 2.
  • This assay was used to test compounds for their ability to inhibit TARP ⁇ 8 dependent AMPA receptor activity.
  • the AMPA receptor is a non-selective cation channel activated by glutamate. Ionotropic glutamate receptors normally desensitize too rapidly to allow detectable calcium influx in a FLIPR assay (Strange et al. (2006). “Functional characterisation of homomeric ionotropic glutamate receptors GluR1-GluR6 in a fluorescence-based high throughput screening assay.” Comb Chem High Throughput Screen 9(2): 147-158). But, this desensitization is incomplete, and a substantial steady-state current remains in the sustained presence of glutamate (Cho et al. (2007). “Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents.” Neuron 55(6): 890-904).
  • Channels expressed with this construct appear to have similar properties to channels formed by co-expression of GRIA1o with an excess of CACNG8 (Shi et al. 2009).
  • Cell expressing the GRIA1o-CACNG8 fusion construct were grown in a monolayer in 96- or 384-well microtiter plates.
  • the fluorescence in each well was normalized to the fluorescence of negative and positive control wells.
  • the negative control wells had no added compounds, and the positive control wells had been incubated with 10 ⁇ M CP465022 (a non-subtype-selective AMPA receptor antagonist) (Lazzaro et al. (2002). “Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist.” Neuropharmacology 42(2): 143-153).
  • the responses to glutamate as functions of the test compound concentrations were fitted to a four-parameter logistic function.
  • the fitted parameter corresponding to the midpoint was taken to be the potency of inhibition of the compound.
  • Table 4 illustrates the observed potentcy for the compounds described herein.
  • pIC 50 refers to the negative log of the IC 50 in molar.
  • Hippocampi were dissected from C57black6 mice at 4-12 weeks postnatal, following the protocol described by Brewer (Brewer, G. J. (1997). “Isolation and culture of adult rat hippocampal neurons.” Journal of Neuroscience Methods 71(2): 143-155). The following is a brief summary of the procedure. Mice were asphyxiated with CO 2 then decapitated. The brain was rapidly removed, then placed into ice-cold HABG medium. The recipe for HABG medium was: HibernateA supplemented with 2% B27 and 0.5 mM Glutamax (all reagents from Life Technologies). Hippocampi were micro-dissected from the brains, then washed with HABG without calcium (Hibernate A minus Calcium, BrainBits; 2% B27, Life Technologies; 0.5 mM glutamax, Life Technologies).
  • the hippocampi were then transferred to HABG without calcium, supplemented with 2 mg/mL papain (Worthington Biochemical). They were incubated at 30° C. on a roller for 40 min, then gently triturated with a fire-polished glass pipette. The supernatant containing dissociated neurons was collected, then centrifuged for 2 min at 200 g. The cell pellet was collected, and then resuspended in 8 mL of HABG. Live cells were counted, then plated onto 12 mm glass coverslips in HABG (2 mL) in 24-well plates at a density of 50-100 cells per coverslip. These cells were maintained at room temperature until use.
  • the intracellular buffer was 90 mM KF, 30 mM KCl, 10 mM HEPES, and 5 mM EGTA, pH 7.4, 290 mOs.
  • the extracellular buffer was 135 mM NaCl, 4 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 5 mM glucose, 10 mM HEPES, pH 7.4, 300 mOs.
  • the open-tip resistances of the micropipettes using these solutions were 2-4M ⁇ .
  • Whole-cell recordings of neuron cell bodies were performed in voltage-clamp mode using an Axon Axopatch 200B amplifier.
  • Whole-cell current was measured holding the interior of the cell at ⁇ 60 mV, using a 5 kHz lowpass filter.
  • the cells were continuously perfused through 7 mm square glass barrels using a solenoid-controlled solution switching device (Warner Instruments, PF-77B).
  • the peak current in response to a 500 ms exposure to 10 mM glutamate every 5 seconds was measured, before and after exposure to test compound.
  • the mean peak current of 5 traces in the presence of test compound was divided by the mean peak current of 5 traces prior to the addition of test compound.
  • Compounds were tested at concentrations at least ten times higher than their estimated potency in the calcium flux assay, in order to ensure near-saturating occupancy of the receptor.

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